The main psychoactive compound of marijuana, (-9-tetrahydrocannabinol (THC) has been shown to suppress host resistance to bacterial, viral and parasitic infections, presumably through the central or peripheral cannabinoid receptors, CB1R or CB2R, respectively. While CB1R is abundant in the central nervous system, CB2R is mainly expressed in immune cells. The effect of THC on Legionella pneumophila (L.p.) infection has been thoroughly studied by others. They found that THC suppressed T helper1 (Th1) cytokines (i.e interferon-3 (IFN- 3)) while increasing Th2 cytokines (i.e. interleukin-4 (IL-4)). However the effect of cannabinoids on fungal infections is unknown. The goal of the present proposal is to investigate the effects of cannabinoids (THC and 2-arachidonoylglycerol (2-AG)) and CB2R on a systemic Candida albicans (C. albicans) infection. C. albicans is the most common cause of systemic candidiasis, an infection that occurs frequently in immune compromised individuals (i.e., patients with AIDS), who may use marijuana to combat emesis and anorexia. Systemic candidiasis may also occur in immune competent individuals (i.e. patients with in-dwelling catheters). In the first aim of this proposal, we will investigate the role of cannabinoids and CB2R on the innate immune response to Candida infection. In the second aim, we will examine the effects of cannabinoids and CB2R on the adaptive immune response to the infection. To address the first aim, we will treat each wild type (WT) or CB2R knockout (CB2R-/-) mouse with vehicle or cannabinoids and 18h later will inject the mice with PBS or C. albicans (1x107 yeast). We will then collect serum, kidneys and spleens 2h, 8h and 1 day after the yeast infection. Others have shown that the acute phase cytokines (i.e. interleukin-6 (IL-6), tumor necrosis- 1 (TNF- 1) and IFN- 3) are elevated in the serum of C. albicans infected mice. We will compare serum cytokine and splenic macrophages cytokine mRNA levels from cannabinoid and vehicle treated mice using enzyme linked immunosorbent assay and real time RT-PCR, respectively. To address the second aim of this study, WT or CB2R-/- mice will receive vehicle or cannabinoids and 18h later will be injected with PBS or C. albicans (0.75- 1x106 yeast). To study the primary immune response, some of the mice will be sacrificed 1 day, 3 days and 7 days later to determine serum IFN-3 and IL-4 levels. Fifteen days after the 1st C. albicans dose, the remaining mice will receive a higher dose of C. albicans (1-2x107 yeast). Half of these mice will be housed for up to 14 days to investigate the effect of cannabinoids on the memory immune response. The remaining mice will be sacrificed 2h, 8h and 1 day after the 2nd yeast challenge to determine serum and splenic T cell IFN-3 and IL-4 protein and mRNA levels, respectively. Weight and morbidity will be monitored daily for all mice. Kidneys or spleens will be collected at the different time points to evaluate the level of infection by counting the yeast colony forming units. We expect that cannabinoids will alter the innate and adaptive immune responses to the fungal infection. If cannabinoids act via CB2R, cannabinoids will not alter the fungal infection in CB2R-/- mice. Public Health Relevance: Systemic Candida albicans yeast infections are common among AIDS, cancer and transplant patients, individuals who may use marijuana and related compounds, such as Marinol (delta-9-tetrahydrocannabinol (THC)), to combat emesis and anorexia. THC is known to suppress immunity to bacterial, viral and parasitic infections, but its effect on yeast infections is essentially unknown. The present proposal will investigate the effects of THC, its related compound 2-arachidonoylglycerol and the peripheral cannabinoid receptor on the immune responses to a systemic Candida albicans infection in mice.